Fibroblast Growth Factor Receptor 3 (FGFR3) is one member of a family of receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, FGFR4) that binds fibroblast growth factors (FGFs) (Keegan et al. (1991) PROC. NATL. ACAD. SCI. USA 88:1095-1099). FGF receptors are characterized as having three extracellular immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. FGF ligand binding induces FGF receptor dimerization and tyrosine autophosphorylation resulting in cell proliferation, differentiation, and migration (Gomez-Roman et al. (2005) CLIN. CANCER RES. 11:459-65; Chang et al. (2005) BLOOD 106:353-6; Eswarakumar et al. (2005) CYTOKINE GROWTH FACTOR REV. 16(2): 139-49).
Alternative splicing of the FGFR3 transcript results in two isoforms, IIIb and IIIc. The FGFR3 isoforms are differentially expressed with epithelial cells expressing predominantly the IIIb isoform, whereas fibroblast cells express a mixture of IIIb and IIIc transcripts (Scotet et al. (1995) BIOCHIM. BIOPHYS. ACTA 1264:238-42). In addition, the IIIb and IIIc splice variants differ in their specificity for FGF ligand. The IIIb splice variant has high affinity for FGF1 (acidic FGF) ligand and lower affinity for FGF8 (androgen-induced growth factor) and FGF9 (glial activating factor) (Chellaiah et al. (1999) J. BIOL. CHEM. 274:34785-94; Gomez-Roman et al. (2005) supra). The IIIc splice variant is characterized as a promiscuous receptor binding numerous FGF ligands including FGF1, FGF2, FGF4, FGF8, FGF9, FGF16, FGF17, FGF18, FGF19, FGF20, FGF21, and FGF23 (Chellaiah et al. (1994) J. BIOL. CHEM. 269:11620-7; Gomez-Roman et al. (2005) supra; Ornitz et al. (1996) J. BIOL. CHEM. 271(25):15292-7; Lee et al. (2000) J. BIOL. CHEM. 275(43):33679-87).
The FGFR3-FGF signaling pathway plays a role in the differentiation of adipocytes, chondrocytes and neurons, wound healing, angiogenesis, embryo development, and malignancies (Keegan et al. (1991) supra). Activating mutations of FGFR3 have been associated with cancer and skeletal disorders including dwarfism, achondroplasia, and hypochondroplasia (Gomez-Roman et al. (2005) supra; Delezoide et al. (1997) HUMAN MOL. GENETICS 6:1899-1906). Certain FGFR3 antibodies are known. See, e.g., U.S. 2005/0147612 (Yayon).
Antibodies are multimeric proteins that contain four polypeptide chains (FIG. 1). Two of the polypeptide chains are called heavy chains (H chains), and two of the polypeptide chains are called light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (VL in FIG. 1) and one constant region (CL in FIG. 1). The heavy chain consists of one variable region (VH in FIG. 1) and at least three constant regions (CH1, CH2 and CH3 in FIG. 1). The variable regions determine the specificity of the antibody.
Each variable region comprises three hypervariable regions also known as complementarity determining regions (CDRs) flanked by four relatively conserved framework regions (FRs). The three CDRs, referred to as CDR1, CDR2, and CDR3, contribute to the antibody binding specificity.
Although certain anti-FGFR3 antibodies are known in the art, there is still a need for additional FGFR3 modulators that can be used as therapeutic and diagnostic agents.